Hofmeyr_Use of Calcium and Vitamin D for Prevention

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Use of calcium and vitamin D forprevention of pre-eclampsia/eclampsiaJustus Hofmeyr, for the Calcium and Pre-eclampsia

(CAP) Study Group**Fernando Althabe, John Anthony, Jos Belizn,

Eduardo Bergel, Ana Pilar Betran, Eckhart Buchmann,Gabriela Cormack, Sue Fawcus, Justus Hofmeyr,Stephen Munjanja, Adegboyega Oyebajo, Diane

Sawchuck, Mandisa Singata, Peter von Dadelszen Effective Care Research Unit, University of the

Witwatersrand, Fort Hare and Eastern Cape

Department of Health


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p


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Mdantsane, Eastern Cape(near East London, South Africa)


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Labour ward, Cecilia Makiwane Hospital


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Outline: Vitamin D and pre-eclampsia:

EpidemiologyRandomized trials

Calcium and pre-eclampsia:EpidemiologyCochrane review of randomized trials

Implications for practice

Research agenda


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Vitamin D and Pre-eclampsia:Epidemiology

Several observational studies have shown anassociation between low Vitamin D intake or serumlevels (25(OH)D)*, and pre-eclampsia, but reportsinconsistent** *Wei S et al. Longitudinal vitamin D status in pregnancy and the

risk of pre-eclampsia BJOG.. 2012 Mar 29

*Woodham PC et al. Midgestation maternal serum 25-hydroxyvitamin D level and soluble fms-like tyrosine kinase1/placental growth factor ratio as predictors of severepreeclampsi.a Hypertension 2011 Dec;58(6):1120-5

**Nassar N et al. Systematic review of first-trimester vitamin Dnormative levels and outcomes of pregnanc.y Am J ObstetGynecol 2011 Sep;205(3):208.e1-7
http://www.ncbi.nlm.nih.gov/pubmed/22462640http://www.ncbi.nlm.nih.gov/pubmed/22462640


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Vitamin D supplementation inpregnancy

Systematic review: 6 small randomized trials (1023 women)

Vit D plus calcium: 400 women

Vit D alone: 623 women Statistically borderline reduction in low birthweight

No data on effect of Vit D alone on Pre-eclampsia

Numbers too small for meaningful analysis

De-Regil LM et al. Vitamin D supplementation for women during

pregnancy. Cochrane Database Syst Rev. 2012 Feb


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Ongoing research

Large trial of Vitamin D supplementation inpregnancy completed (Bhutta et al)

Results expected soon

Watch this space


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In view of the deficiencies of protein,calcium and vitamin B1 in the averageAustralian diet, especially of those who

have toxaemia....


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Hamlin RHJ. Prevention of pre-eclampsia.

Lancet 1962;1:864-865

Hamlin 1962: Experience in Ethiopia


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Market Addis Ababa


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Pre-eclampsia and dietary calcium

Low incidence of pre-eclampsia noted in

Guatemala (Belizan 1980) Postulated due to high calcium diets

Belizan JM, Villar J. The relationship betweencalcium intake and edema, proteinuria, andhypertension-gestosis: an hypothesis.American Journal of Clinical Nutrition1980;33:2202-10.


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Calcium to reduce pre-eclampsia:Cochrane systematic review: 1998

Large reduction in pre-eclampsia in several smallstudies

No significant effect in large US study (CPEP)

? Publication bias

? Different effects in populations with low andadequate dietary calcium

Hofmeyr GJ, Atallah N, Duley L. Calciumsupplementation during pregnancy for preventinghypertensive disorders and related problems. Cochrane

Database of Systematic Reviews 1998


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World Health organization randomized trial ofcalcium supplementation among low calcium intakewomen.

Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, ZavaletaN, Purwar M, Hofmeyr GJ, thi Nhu Ngoc N, CampdonicoL, Landoulsi S, Carroli G, Lindheimer M et al.

Am J Obstet Gynecol

2006;194: 639-649

Revised Systematic

Review :Hofmeyr GJ, Lawrie TA,

Atallah N, Duley L.

Cochrane Database of

Syst Reviews 2010


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Calcium vs Placebo: Pre-eclampsia


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Calcium vs Placebo: Proteinuria


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Calcium vs Placebo: Eclampsia


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Calcium vs Placebo: Maternal Death

l i l b


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Calcium vs Placebo:Maternal death/ severe morbidity

C l i f id


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Calcium: summary of evidence Epidemiological association of dietary calcium with

huge discrepancies in rates of pre-eclampsia/eclampsia

Calcium supplementation in the second half ofpregnancy reducespre-eclamsia ? (but not in largest trial)

Severe morbidity (about 20%)

This benefit is sufficient to justify programs tosupplement pregnant women with low calcium diets

Ongoing research to determine whether pre-pregnancy supplementation will reproduce the moredramatic epidemiological differences

C l i d l i i l


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Calcium and Pre-eclampsia Trial


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Future research: The CAP study The Calcium and Pre-eclampsia study

Randomized trial: calcium 500mg daily vs placebocommencing before conception till 20 weeks

Participants: women with previous pre-eclampsia

who intend to conceive Routine calcium in second half of pregnancy

If effective, next step trials of community level

calcium supplementation by food fortification ? Place of Vitamin D supplementation

Further research on ideal dose

O h b fi d i k f


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Other benefits and risks ofcalcium supplementation

Reduced hypertension Reduced osteoporosis

Reduced Urinary stones

Improved insulin sensitivity in type 2 diabetes

? Reduced colorectal cancer

? Increased risk of coronary artery disease if doseexcessive

Tablets a bit expensive, and heavy to transport

O i f l i l i


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Options for calcium supplementationprograms

Individual supplementation during pregnancy(limited to antenatal care attenders):All pregnant women

Individuals/populations with low calcium diet

Women at high risk of pre-eclampsia (Nulliparous,previous pre-eclampsia, risk factors, screening, etc)

?consider lower dosage eg 500mg/day

Population supplementation: fortification of staplefoodsBroad population coverage, except peoplewho grow their own food.

Population dietary education


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D il i i l l f l i


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Daily provisional supply of calciumper capita in developing and developed

countries (FAO, 1990)

REGION CALCIUM (mg)

World

Developed countries

Developing countries

Africa

Latin America

Near East

Far East

Others

472

860

346

363

499

498

352

402


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Calcium vs Placebo: HELLP syndrome

H h i


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Hypothesis:Calcium supplementation in 2nd half of pregnancy:

blood pressure ( vascular tone) serious complications related to hypertension

No effect on other organ dysfunction eg endothelial

BP early deliveries (induction/CS) low birthweight

time to develop HELLP syndrome

To prevent multisystem dysfunction may need adequatecalcium from before pregnancy

Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation forprevention of pre-eclampsia and related problems: a systematic review

and commentary. BJOG. 2007; 114: 933-943
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17565614&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17565614&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


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Food fortification: Advantages rapid improvements in the micronutrient intake and

status of a population cost-effective public health intervention

if consumed regularly will maintain body stores

fortified staple foods will provide physiologicaldosesof micronutrients

does not require changes in existing food patterns does not depend on compliance

minimal risk of toxicity, when properly designed

and regulated


35/37Lancet 1952 Jan 12;1(6698):64-8 H li 1962 E i i Ethi i


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Hamlin RHJ. Prevention of pre-

eclam sia Lancet 1962 1:864-865

Hamlin 1962: Experience in Ethiopia


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Vitamin D and mortality

Has been suggested that increasing vitamin D levelsis associated with reduceed mortality

Grant WB. An estimate of the global reduction in

mortality rates through doubling vitamin D levels.Eur J Clin Nutr. 2011 Sep;65(9):1016-26.

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